NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors

Author:

Kurelac Ivana12ORCID,Cavina Beatrice1,Sollazzo Manuela3,Miglietta Stefano3,Fornasa Agnese3,De Luise Monica12,Iorio Maria1,Lama Eleonora1,Traversa Daniele3ORCID,Nasiri Hamid Razi4,Ghelli Anna23,Musiani Francesco3,Porcelli Anna Maria235,Iommarini Luisa23ORCID,Gasparre Giuseppe12

Affiliation:

1. Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy

2. Centre for Applied Biomedical Research (CRBA), University of Bologna, Bologna, Italy

3. Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Bologna, Italy

4. Department of Cellular Microbiology, University Hohenheim, Stuttgart, Germany

5. Interdepartmental Centre for Industrial Research ‘Scienze della Vita e Tecnologie per la Salute’, University of Bologna, Bologna, Italy

Abstract

Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.

Funder

Associazione Italiana Ricerca sul Cancro

European Commission

Fondazione Cassa di Risparmio di Bologna

Ministero dell'Università e della Ricerca

Fondazione del Monte di Bologna e Ravenna

Publisher

The Royal Society

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology,General Neuroscience

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